Herpes simplex virus type 1 (HSV-1) is a common cause of acute and recurrent disease in humans. After the primary infection, which usually occurs in childhood, HSV-1 remains dormant in the nervous system. This proposal is aimed at exploring a novel hypothesis that early infection with HSV-1 plays a critical role in the genesis of temporal lobe epilepsy (TLE). The virus may contribute to this by creating a specialized brain focus involving alterations in neural circuitry and formation of a unique glial/microvascular substrate that promotes epileptogenesis and maintenance of seizures. Several observations suggest that HSV-1 may cause TLE. For example, survivors of HSV-1 encephalitis frequently develop epilepsy. HSV-1, when causing encephalitis, preferentially invades and lesions limbic structures, including the hippocampus, which also shows neuropathological changes in TLE. Moreover, patients with medically intractable TLE have a ten times higher rate of latent HSV-1 infection in their hippocampus than control subjects. To evaluate our hypothesis two approaches are proposed. (1) To critically explore the connection between HSV-1 and TLE by assessing the presence of viral DNA (by polymerase chain reaction) and virions (by immunohistochemistry) in surgically resected hippocampi from TLE patients, and correlating these with the specific neuropathological characteristics of TLE, i.e. (a) loss of hilar interneurons, (b) gliosis, and (c) vascular proliferation. (2) To assess the causal relationship of HSV-1 to the development of chronic seizures and neuropathology in TLE, rat models of HSV-1 infection will be studied and experimental modifiers of infection such as (a) viral strain, (b) age, (c) fever/febrile seizures, and (d) acute seizures, will be evaluated. The cellular/molecular mechanisms of viral-induced neuropathology and seizures will be explored by investigating the pattern and time-course of viral invasion during the infection. If a viral causation of TLE is established, then this would not only open new avenues for prevention and control of this disorder, but also improve our understanding of viral-induced brain injury.